Existing Drugs Induce Senescence, Stop Liver Cancer

Two existing drugs, Gemcitabine and DON, target the degradation of nucleotides in the liver.

New research finds that a mutation in the gene Arid1b can cause liver cancer, but fortunately there are 2 existing drugs that can stop this growth in human cells.

Gemcitabine is indicated for the treatment of bladder, ovary, and pancreatic cancer, while the drug DON has been tested in clinical trials. Both drugs have been deemed safe for use in humans, and do not require toxicity testing.

For the study, researchers looked for mutations in DNA of 100 liver cancer patients. Their primary focus was on genes known to regulate the cellular state called senescence, which helps protect the cell against cancer.

When a cell grows at an abnormal rate, senescence becomes activated. Once the process is induced, it works to keep the cell in limbo by keeping it alive, while preventing it from growing or dividing. Many types of cancer are known to bypass senescence.

Studies have suggested that the Arid1b gene plays a role in liver cancer, but the new study, published in Genes and Development, was the first to demonstrate that it contributes to cancer development by disrupting senescence.

Researchers mutated Arid1b in mouse and human cells, preventing the cells from entering senescence. Additionally, when Arid1b was mutated in mice that had a mutation in the Ras gene, they found that the mice developed liver cancer.

The findings suggest that the new treatment will be most effective in individuals who have a mutation in the Arid1b gene, according to the study.

“It’s important to better classify patients in groups, according to their genes,” said researcher Luca Tordella. “One advance of personalized medicine is to understand which drug will work best on you, and which on me.”

The researchers were also able to pinpoint exactly how Arid1b stimulates senescence. In normal and healthy cells, Arid1b is part of the SWI/SNF complex that regulates the activity of hundreds of genes. One gene in particular produces an enzyme that breaks down the building blocks of DNA. Without the blocks, called nucleotides, the cell is unable to continue to grow and divide, causing it to enter senescence.

When the Arid1b gene is mutated the nucleotides are unable to be degraded and it allows the cell to continue to grow. Eventually it bypasses senescence and can potentially grow out of control, according to the study.

Inducing senescence is still possible, however, and researchers were able to demonstrate this with the use of gemcitabine or DON. These drugs are designed to inhibit the synthesis of nucleotides, inducing senescence and stopping cancer growth.

“Around 20% of patients with liver cancer have mutations on the genes encoding for components of the SWI/SNF complex,” said lead researcher Jesus Gil. “What we suggest is if we treat these people with drugs that target the degradation of nucleotides, they will respond. We plan to continue to research this in the lab to develop treatments to target liver cancer.”